Oncogenic cellular transformation and cancer is associated with enhanced PI3K signalling as a result of mutational activation and overexpression of class I PI3K and genetic or epigenetic inactivation of PTEN (Ali et al., J. Natl. Cancer Inst. 1991, 1922-1932; Cantley et al., Science 2002, 296, 1655-1657; Campbell et al., Cancer Res. 2004, 64, 7678-7681; Cully et al., Nat. Rev. Cancer 2006, 6, 184-192; Vogt et al., Trends Biochem. Sci. 2007, 32, 342-349). Phosphatidylinositol 3-kinases (PI3K's), a family of lipid enzymes catalyzes the phosphorylation of the 3-OH of the inositol ring. It has a central role in regulating a wide range of cellular processes including metabolism, survival, motility, differentiation and cell activation (Vanhaesebroeck et al., Annu. Rev. Biochem. 2001, 70, 535). Its estimated that PI3K signalling pathway has 50-100 downstream effectors in every eukaryotic cell. These lipid enzymes are classified into 3 major classes, I, II & III, based on their structure and in vitro substrate specificity (Wymann M. and Pirola L., Biochim. Biophys. Acta 1998, 1436, 127). These class I PI3K kinases include four isoforms: PI3K α, β, γ and δ. Both PI3K α and PI3K β are known to be expressed ubiquitously, while PI3K γ and PI3K δ are restricted mainly to hematopoietic cells (Vanhaesebroeck et al., Proc. Natl. Acad. Sci. USA 1997, 94, 4330-4335). The catalytic subunit of the p110α, p110β and p110δ isoforms is constitutively bound to a p85 regulatory subunit. It's also important to know that only class I isoforms phosphorylate inositol lipids to form second messenger phosphoinositides, specifically converting PIP2 to PIP3 in the cell membrane, which then recruit downstream signaling proteins such as Bruton's tyrosin kinase (Btk), phosphatidylinositol-dependent kinase (Pdk), GRP1 and Akt (Vanhaesebroeck et al., Nat. Rev. Mol. Cell. Biol. 2010, 11, 329-41; Cantrell et al., J. Cell. Sci. 2001, 114, 1439-45; Ju He et al., J. Lipid Res. 2008, 48, 1807-1815). The activation of PI3K pathway is not only via RTKs, but also by RAS and GPCR (Irene Brana and Lillian L Siu., BMC Medicine 2012, 10, 161). The activation of PI3K pathway by RAS protein is by direct interaction with p110α, p110γ, and p110δ subunits, while GPCRs can interact with p110β and p110γ subunits (Vanhaesebroeck et al., Nat. Rev. Mol. Cell Biol. 2010, 11, 329-341).
The mode of regulation by upstream signalling also differs among the four PI3K isoforms. The γ isoform is linked to G protein-coupled receptors, whereas the PI3K α and PI3K δ isoforms are activated by signals from receptor tyrosine kinases. However the PI3K β isoform can accept input from both receptor tyrosine kinases and from G protein-coupled receptors (Kang et al., Proc. Natl. Acad. Sci. USA 2006, 103, 1289-94).
PI3K activity is functionally antagonized by phosphatase and tensin homolog (PTEN), a tumor suppressor gene that encodes a lipid phosphatase that removes the phosphate from the 3-OH position of 3-phosphoinositides, reducing the cellular pool of PI(3,4,5)P3 by converting it back to PI(4,5)P2 (Liu et al., Nat. Rev. Drug Discov. 2009, 8, 627-44). Loss of PTEN expression has been shown to activate the PI3K/Akt/mTOR pathway and also correlates with poor prognosis and thereby reduced survival in human cancer (LoPiccolo et al., Drug Resist. Updat. 2008, 11, 32-50).
PIK3CA mutations are reported in several cancer types, including glioblastoma multiforme, breast cancer, endometrial cancer, colorectal cancer and hepatocellular carcinoma. PIK3CA mutations are oncogenic per se promoting tumor formation in several preclinical models without other molecular aberrations (Ikenoue et al., Cancer Res. 2005, 65, 4562-4567; Isakoff et al., Cancer Res. 2005, 65, 10992-11000; Zhao et al., Proc. Natl. Acad. Sci. USA 2005, 102, 18443-18448). PI3Kα is the most frequently found mutated isoform in human cancers. It's reported that in PIK3CA gene, 80% of the mutations are clustered at three hotspots in the p110α gene that encodes the catalytic subunit: two in the helical domain (E542K and E545K) and one in the kinase domain (H1047R) (Zhao et al., Oncogene 2008, 27, 5486-5496). However these somatic mutations are clustered in two hot spots: exon 9 in the helical domain of p110α are common in colorectal cancer, cervical squamous and squamous cell cancer of head and neck and exon 20 in the kinase domain of p110α are common in uterine, breast cancer and ovarian cancers (Janku et al., PLOS One 2011, 7, 6).
The non-alpha isoforms of class I PI3K have no cancer-specific mutations, but their differential expression has been observed in several cancers. Reported data also suggests involvement of non-alpha isoforms of class I PI3K in solid tumors. Recent studies show that certain PTEN-deficient human cancer cell lines are sensitive to inactivation of p110β rather than p110α (Wee et al., Proc. Natl. Acad. Sci. USA 2008, 105, 13057-62; Torbett et al., Biochem. J. 2008, 415, 97-110). In vivo studies however suggest that p110δ isoform-specific targeting may be cytotoxic to B cells with minimal toxicity to other hematopoietic cell types. To clearly understand the functional role of p110δ in B cells, forced expression of p110δ was found to enhance transforming potential in cell lines (Kang et al., Proc. Natl. Acad. Sci. USA 2006, 103, 1289-94). In acute myeloblastic leukemia, p110δ isoform is consistently overexpressed and p110δ inhibitors specifically interfere with the growth of these leukemic cells, suggesting a role for p110δ in leukemogenesis (Samuels et al., Science 2004, 304, 554; Sujobert et al., Blood 2005, 106, 1063-6). However, P110γ is specifically overexpressed in human pancreatic intraepithelial neoplasia and ductal carcinoma, which correlates with increased levels of PIP3 and phosphorylated Akt (Edling et al., Clin. Cancer Res. 2010, 16, 4928-4937; El Haibi et al., Mol. Cancer 2010, 9, 85). Increased expression of p110γ is also seen in chronic myeloid leukemia (Hickey and Cotter., J. Biol. Chem. 2006, 281, 2441-50; Knobbe et al., Neuropathol. Appl. Neurobiol. 2005, 31, 486-90).
Hence, it is evident that class I PI3Ks are involved in survival mechanism and progression of many cancer types and therefore is one among the most sought after targets in cancer therapeutics. So, targeting PI3K itself or downstream effectors of PI3K is an approach that has the potential to be of huge therapeutic benefit.